Even if discovered at stage I and surgically removed, lung adenocarcinomas can relapse within months, spreading to lymph nodes, the contra-lateral lung, brain, bones, and the adrenal glands. The genetic determinants and molecular mechanisms involved in lung adenocarcinoma metastasis are obscure. During the previous grant period, the Massague group (RP1) began to clarify these issues. The work revealed a link between WNT and pulmonary tumor progression, identified a lung WNT gene signature (LWS) that predicts distant relapse in lung adenocarcinoma tumors ofany stage, provided tractable experimental models for bone and brain metastasis by lung adenocarcinoma cells, and uncovered H0XB9 as a WNT target gene that enhances tumor re-initiation in brain and bone marrow. Based on this progress. Aims 1 and 2 RPl in this competing renewal will seek to identify genes and pathways that support the viability of lung adenocarcinoma micrometastases, with the goal of providing information to target such pathways in the adjuvant setting after resection in order to prevent metastasis. Aim 3 in RP1 will build on this lab's recent progress in brain metastasis by focusing on the role of Serpins in this process, in particular Neuroserpin, a brain-specific member ofthis family of secreted protease inhibitors. RPI's preliminary data demonstrate that lung adenocarcinoma cells express Neuroserpin as a mediator of brain colonization, and that Neuroserpin is highly expressed in at least one-half of the human lung adenocarcinoma brain metastases that have so far been examined by immunohistochemistry. Other data from the Massague lab has recently shown that S100A8/9 are mediators of metastasis-linked chemoresistance in nfiouse models, and that S100A8 is amplified and highly expressed in human lung adenocarcinoma samples. Aim 4 in RPl proposes to investigate the role of S100A8/9 in lung adenocarcinoma metastasis and response to chemotherapy, with the goal of uncovering new ways to augment the efficacy of targeted and conventional chemotherapies in lung cancers.